Boron neutron capture therapy (BNCT) is a bimodal radiation treatment for cancer treatment. 10B-rich tumors are irradiated with low-energy (e.g., thermal or epithermal) neutrons. A 10B nucleus absorbs a neutron and ejects an energetic (1.47 MeV) α particle (4He2+), a 0.84 MeV lithium ion (7Li3+), and a 0.48 MeV γ-ray. The 10B(n, α)7Li nuclear reaction products are highly damaging to tumor cells through ionization processes, yet are of sufficiently low energy that they lie in the “Linear Energy Transfer” (LET) regime. See generally Barth, R. F., Soloway, A. H., Fairchild, R. G. & Brugger, R. M., Cancer, 1992, 70, 2995-3007; and Barth, R. F., Soloway, A. H., Goodman, J. H., Gahbauer, Fairchild, R. A, Gupta, N., Blue, T. E., Yang, W. & Tjarks, W., Neurosurg. 1999, 44, 433-451; and R. Barth et al., “Boron Neutron Capture Therapy of Cancer: Current Status and Future Prospects,” Clin. Canc. Res., vol. 11, pp. 3987-4002 (2005); and published international patent application WO 01/85736. The nuclear reaction's energy E is nearly linear with distance x from the irradiated 10B nucleus, and dE/dx is large and negative. Cytotoxic ions resulting from the 10B(n, α)7Li nuclear reaction travel only approximately 5 to 9 μm, about one cell diameter, effectively limiting toxicity to the cell in which the 10B nucleus was irradiated, and perhaps its nearest neighbors. BNCT has the potential for selectively targeting and destroying malignant cells in the presence of normal cells, provided a tumor-selective 10B-delivery drug is available. Such localized cancer therapies are particularly attractive for (but are not limited to) the treatment of high-grade gliomas and metastatic brain tumors, which infiltrate the brain, and for which selective tumor destruction could dramatically increase patient life quality and expectancy.
While 10B is not the only nuclide with a large neutron capture cross section, it is considered promising for neutron capture therapy due to the LET localization of the 10B(n, α)7Li reaction's cytotoxic products, the nearly 20% abundance of 10B in naturally-occurring boron, boron's own non-radioactivity, and finally its chemical facility. It is possible to obtain boron compounds that are enriched in 10B up to 98%.
Exploitation of the 10B(n, α)7Li reaction products' localized damage relies upon the preferential uptake of boron by tumor cells over that by healthy cells so that a concomitantly higher dose will be delivered during neutron irradiation. See Hawthorne, M. F., Mol. Med. Today, 1998, 4, 174-181; and Hawthorne, M. F., Angew. Chem. Int. Ed. Engl., 1993, 32, 950-984.
Two compounds, disodium mercapto-closo-dodecaborate (BSH) and L-4-dihydroxy-borylphenylalanine (BPA), have recently been employed in clinical trials in the United States, Europe, and Japan in patients with glioblastomas and melanomas. See Kageji, T., Nakagawa, Y, Kitamura, K., Matsumoto, K. & Hatanaka, H. J., Neurooncol. 1997, 33, 117-130; Pignol, J.-P., Oudart, H., Chauvel, P., Sauerwein, W, Gabel, D. & Prevot, G. Br. J. Radiol., 1998, 71, 320-323; and Elowitz, E. H., Bergland, R. M., Coderre, J. A, Joel, D. D., Chadha, M. & Chanana, A. D., Neurosurgery, 1998, 42, 45 463-469. BSH and BPA yield tumor: blood boron concentration ratios of about 1:1 and about 3:1, respectively. There is an unfilled need for new 10B carriers with improved tumor selectivity.
Porphyrins and related macrocycles tend to accumulate preferentially in neoplastic tissue over healthy tissue. See Bonnett, R. Chem. Soc. Rev., 1995, 24, 19-33.
Porphyrins are also useful in another therapeutic method, photodynamic therapy (PDT) of tumors. See Schnitmaker, J. J., Bass, P., van Leengoed, M. L. L. M., van der Meulen, F. W., Star, W. M. & van Zaudwijk, N.J., Photochem. Photobiol B: Biol., 1996, 34, 3-12; and Dougherty, T. J., Gomer, C. J., Henderson, B. W., Jori, G., Kessel, D., Korbelik, M., Moan, J. & Peng, Q. J., Natl. Cancer Inst., 1998, 90, 889-905. PDT relies upon the selective uptake into tumor tissues of the compound, which will now act as a photosensitizer. After tissue uptake, irradiation with light causes the generation of highly-reactive singlet oxygen (1O2) and other cytotoxins. For example, Photofrin® is an FDA-approved, porphyrin derivative that has been used in photodynamic therapy for cancers of the lung, digestive tract, and genitourinary tract.
Another porphyrin-based drug, Visudyne™, has been approved by the FDA to suppress the development of choroidal neovascular membranes, the leaky vascular structures that cause age-related (“wet”) macular degeneration of the eye. The 1O2 coagulates blood within the neovascular network, thereby clogging and killing it.
Some porphyrins also appear to suppress cancer by a mechanism less harsh than oxidatively-driven necrosis, and instead to induce apoptosis, the orderly shutdown, death, and absorption of cells mediated by the immune system. This mechanism appears to work either upon irradiation with light, particularly at low levels, or by mere accumulation of high drug levels in tissues, even without light irradiation. See Luo Y, Chang, C. K. & Kessel, D., Photochem. Photobiol. 1996, 63, 4, 528-534; Luo Y & Kessel, D., Photochem. Photobiol. 1997, 66, 4, 479-483. The ability of porphyrin-derived drugs to induce apoptosis may enhance the effectiveness of both PDT and BNCT cancer treatments.
A potential advantage of epithermal neutron-based BNCT over PDT is that, while the red light required for PDT penetrates only several millimeters in tissue, epithermal neutrons penetrate effectively to depths of 5-7 cm. Another distinguishing aspect of BNCT is that the energetic 7Li and α particles formed by the neutron capture reaction do not require oxygen to maximize their toxicity, and can mitotically disable quiescent malignant cells in poorly oxygenated parts of a tumor. However, PDT has the advantage of using readily-available and relatively safe laser radiation. Furthermore, significantly lower doses of porphyrin are required for PDT than for BNCT.
M. Vicente, “Porphyrin-based sensitizers in the detection and treatment of cancer: recent progress,” Curr. Med. Chem., vol. 1, pp. 175-194 (2001) provides a review of the use of porphyrins for cancer detection and treatment by photodynamic therapy, boron neutron capture therapy, radiation therapy, and magnetic resonance imaging.
M. Vicente et al., international patent application WO 01/85736 (2001), discloses the use of certain porphyrin-based compounds for BNCT. See also M. Vicente et al., “Syntheses and preliminary biological studies of four meso-tetra[(nido-carboranylmethyl)phenyl]porphyrins,” Bioorganic & Medicinal Chem., vol. 10, pp. 481-492 (2002); A. Maderna et al., “Synthesis of a porphyrin-labeled carboranyl phosphate diester: a potential new drug for boron neutron capture therapy of cancer,” Chem. Commun., pp. 1784-1785 (2002); M. Vicente et al., “Syntheses of carbon-carbon linked carboranylated porphyrins for boron neutron capture therapy of cancer,” Tetr. Lett., vol. 41, pp. 7623-7627 (2000); and M. Vicente et al., “Synthesis, dark toxicity and induction of in vitro DNA photodamage by a tetra(4-nido-carboranyl)porphyrin,” J. Photochemistry and Photobiology. Vol. 68, pp. 123-132 (2002).